scholarly journals BIOLOGICAL SCIENCES: Neuroscience, cell biology MTSS1/Src family kinase Dysregulation Underlies Multiple Inherited Ataxias

2018 ◽  
Author(s):  
Alexander S. Brown ◽  
Pratap Meera ◽  
Banu Altindag ◽  
Ravi Chopra ◽  
Emma Perkins ◽  
...  
Keyword(s):  
Cell Death ◽  
Nervous System ◽  
Mouse Models ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Purkinje Neuron ◽  
Purkinje Neurons ◽  
Spinocerebellar Ataxias ◽  
Firing Rates ◽  
Protein Levels

AbstractThe genetically heterogeneous Spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of non-receptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-Metastasis (MTSS1) is a novel ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically-approved Src inhibitor corrects Purkinje basal firing, and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression.Significance StatementThe Src family of non-receptor tyrosine kinases (SFK) are essential for nervous system function, and may contribute to neurodegeneration. Spinocerebellar ataxias (SCAs) are neurodegenerative diseases where Purkinje neurons fire irregularly and degenerate leading to motor problems. We show that the SFK suppressor Missing-in-Metastasis (MTSS1) is a novel ataxia gene that links multiple SCAs. MTSS1 loss results in increased SFK activity, degenerating Purkinje neurons with low basal firing rates, and cell death. Surprisingly, mouse models for three different SCAs show elevated SFK activity, with SCA1 and SCA2 models displaying dramatically reduced MTSS1 protein levels. Treatment of each SCA model with SFK inhibitor corrects Purkinje basal firing, and delays ataxia progression in MTSS1 mutants. Our results identify a common link among disparate neurodegenerative diseases.

scholarly journals MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias

2018 ◽  
Vol 115 (52) ◽  
pp. E12407-E12416 ◽  
Author(s):  
Alexander S. Brown ◽  
Pratap Meera ◽  
Banu Altindag ◽  
Ravi Chopra ◽  
Emma M. Perkins ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tyrosine Kinases ◽  
Protein Translation ◽  
Purkinje Neuron ◽  
Spinocerebellar Ataxias ◽  
Firing Rates ◽  
Protein Levels ◽  
Src Inhibitor ◽  
Inherited Ataxias ◽  
Nonreceptor Tyrosine Kinases

The genetically heterogeneous spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of nonreceptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-metastasis (MTSS1) is an ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically approved Src inhibitor corrects Purkinje neuron basal firing and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression.

scholarly journals Receptor Tyrosine Kinases: Role in Cancer Progression

2006 ◽  
Vol 13 (5) ◽  
pp. 191-193
Author(s):  
V. Sangwan ◽  
M. Park
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cancer Progression ◽  
Tyrosine Kinases ◽  
Normal Tissue ◽  
Receptor Tyrosine Kinases ◽  
Tight Control ◽  
Tissue Patterning

Tight control of cell proliferation and morphogenesis in conjunction with programmed cell death (apoptosis) is required to ensure normal tissue patterning. [...]

The Role of FGFR in the Progression of Waldenstrom's Macroglubulinemia and the Effect of Its Inhibition by TKI-258.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3737-3737
Author(s):  
Feda Azab ◽  
Abdel Kareem Azab ◽  
Aldo M. Roccaro ◽  
Antonio Sacco ◽  
Phong Quang ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Cell Death ◽  
Cell Line ◽  
Dose Response ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Therapeutic Window ◽  
Low Grade ◽  
Pi3k Signaling ◽  
Healthy Donors

Abstract Abstract 3737 Poster Board III-673 INTRODUCTION Waldenström macroglobulinemia (WM) is a low grade non-Hodgkin lymphoma, characterized by the presence of abnormal lymphoplasmacytic cells producing high levels of IgM. Although indolent, WM remains incurable, and therefore, there is an urgent need for rationally designed therapy in WM. Receptor tyrosine kinases (RTKs) are cell surface receptors for growth factors, cytokines and hormones which have a critical role in the development and progression of many types of cancer. However, their role in WM was not identified. TKI-258 (Novartis, Basel, Switzerland) is an ATP-competitive inhibitor with activity against (multiple) receptor tyrosine kinases including FGFR and other RTKs. We hypothesized that FGFR is up-regulated in WM and plays a major role in its progression; and that TKI-258 would reduce tumor progression in WM. METHODS AND RESULTS We tested the expression of FGFR3 on WM cells and found overexpression of this RTK compared to CD19+ cells from healthy donors. The activation of FGFR3 by recombinant FGF induced MAPK signaling pathway in WM cells including phosphorylation of RAF, ERK and STAT3. Also it induced PI3K signaling including phosphorylation of AKT, S6R and GSK3. TKI-258 inhibited the FGF induced activation of the MAPK and PI3K signaling pathways in a dose- response manner. Using MTT assay we tested the effect of TKI-258 ( 0 to 2.5 uM) on the survival of WM cell line BCWM-1, on IgM secreting cell line MEC-1, and on CD19+ cells selected from WM patient sample. We found that the TKI-258 induced cell death in all sample tested with an IC50 ranging 0.8-1 uM. Testing the effect of TKI-258 on the survival of CD19+ cells selected from peripheral blood or mononuclear cell from healthy donors showed a minimal effect of less than 10% cell death. These results provide a wide therapeutic window for the use of TKI-258 in WM. Moreover, we tested the effect of TKI-258 on the apoptosis of WM cells by flow cytometry using the apoptosis marker APO-2.7, and found that TKI-258 induced apoptosis of WM cells in a dose-response manner at both 24 and 48 treatment. Moreover these results were confirmed by testing changes in the expression of apoptosis related proteins in response to TKI-258 by immunoblotting, including induction of PARP, and caspase-3 and caspase-9 cleavage. In correlation with these results, cell cycle analysis by PI staining and analysis by flow cytometry of WM cells treated with TKI-258 for 24 hrs showed induction of sub-G1 increase in a dose response manner with an IC50 about 1uM. To test the effect of TKI-258 on the interaction of WM cells with the microenvironment we examined the effect of TKI-258 on adhesion of WM cells to fibronectin and bone marrow stromal cells (BMSCs), and found that TKI-258 induced a 50% decrease of adhesion. Moreover, we found no effect on the chemotaxis of WM induce by stroma derived factor-1 (SDF1). To test the direct effect of TKI-258 on the interaction with the microenvironment, we examined the proliferation of WM when cultured alone of in co-culture with BMSCs by 3H-thymidine uptake assay. We showed that TKI-258 inhibited the proliferation of WM cells with an IC50 of 0.8 uM, in the presence or absence of BMSCs. CONCLUSION In conclusion, we found an overexpression of FGFR3 in WM cells compared to CD19+ cells from healthy donors, and that TKI-258 inhibited the activation of proliferative pathways induced by activation of FGFR3 and led to inhibition of proliferation and apoptosis of WM cells. Disclosures: Ghobrial: Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.

scholarly journals A Knockout of the Tsg101 Gene Leads to Decreased Expression of ErbB Receptor Tyrosine Kinases and Induction of Autophagy Prior to Cell Death

PLoS ONE ◽  
2012 ◽  
Vol 7 (3) ◽  
pp. e34308 ◽  
Author(s):  
Chantey R. Morris ◽  
Marissa J. Stanton ◽  
Karoline C. Manthey ◽  
Keon Bong Oh ◽  
Kay-Uwe Wagner
Keyword(s):  
Cell Death ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Erbb Receptor
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